The present invention relates to a novel indole derivative and medical applications thereof.
Nowadays, opioid receptors are classified into three types: xcexc, xcex4, and xcexa. Among these, research on the xcex4 opioid receptor was behind that regarding receptors of other types. Recently, however, several ligands selective to the xcex4 opioid receptor have been developed, and pharmacological actions relating to the xcex4 opioid receptor have become elucidated. Examples of known pharmacological actions relating to the xcex4 opioid receptor include analgesic, antitussive, immunosuppressive, and brain-cell-protecting actions.
Although xcexc opioid agonists, represented by morphine, have been used as analgesics, xcexc agonists have serious xcexc opioidergic side effects such as drug dependence, suppression of the CNS, respiratory depression, or constipation. Also, since codeine, which is known as a typical antitussive, is related to the xcexc opioid receptor, the aforementioned side effects are of serious concern. Antitussive actions of xcexa opioid agonists are also known, although the xcexa opioid agonists have side effects such as drug aversion or psychotomimetic effects. Although analgesic actions of the xcex4 opioid agonists have been reported, they are highly unlikely to show serious side effects compared to those of xcexc and xcexa opioid agonists.
As mentioned above, there are several known pharmacological actions relating to the xcex4 opioid receptor. With the use of the xcex4 receptor ligands as therapeutic agents for various diseases, separation from side effects such as drug dependence or psychotomimetic effects relating to xcexc and xcexa opioid receptors can be expected. Under these circumstances, the development of ligands selective to xcex4 opioid receptors has been proceeding, and agents that act on the xcex4 opioid receptor with higher affinity and higher selectivity are desired.
Known xcex4 ligand compounds are those described in WO 97/11948, etc. For example, WO 97/11948 describes a compound represented by general formula (I) according to the present invention, wherein R1 represents cyclopropylmethyl, R2 represents a hydroxy group, R3 represents a methoxy group, R10 and R11 are bound to each other to form xe2x80x94Oxe2x80x94, xe2x80x94Zxe2x80x94represents xe2x80x94 CH2CH2CH2xe2x80x94, and m and n are each 0. In the present invention, the introduction of hydroxy and/or oxo as R4 and/or R5 can lower metabolic rate. This enables excellent drug efficacy to be sustained for a long period of time, and thus, frequency of administration can be reduced.
An object of the present invention is to provide a xcex4 opioid receptor-selective ligand that can be used as an analgesic, antitussive, immunosuppressive, or brain-cell-protecting agent without serious side effects such as drug dependence, suppression of the CNS, or drug aversion relating to the xcexc and xcexa opioid receptors.
The present inventors have conducted concentrated studies in order to attain the above object. As a result, we have found an indole derivative that acts with high selectivity on the xcex4 opioid receptor, thereby completing the present invention. More specifically, the present invention provides an indole derivative represented by general formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical comprising the same: 
wherein R1 is hydrogen, C1-5 alkyl, C4-7 cycloalkylalkyl, C5-7 cycloalkenylalkyl, C6-12 aryl, C7-13 aralkyl, C3-7 alkenyl, furan-2-yl-alkyl (wherein the alkyl moiety is C1-5), or thiophen-2-yl-alkyl (wherein the alkyl moiety is C1-5);
R2 is hydrogen, hydroxy, C1-5 alkoxy, or C1-5 aliphatic acyloxy;
R3is hydrogen, hydroxy, C2-5 alkoxy, C1-5 aliphatic acyloxy, or C7-13 aralkyloxy;
xe2x80x94Zxe2x80x94 is a crosslinkage having 2 to 5 carbon atoms;
m is an integer from 0 to 3;
n is an integer from 0 to 10;
m number of R4 groups and n number of R5 groups are independently fluoro, chloro, bromo, iodo, nitro, C1-5 alkyl, hydroxy, C1-5 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, isothiocyanato, SR6, SOR6, SO2R6, (CH2)pOR6, (CH2)pCO2R6, SO2NR7R8, CONR7R8, (CH2)pNR7R8, or (CH2)pN(R7)COR8, (wherein p is an integer from 0 to 5; R6 is hydrogen or C1-5 alkyl; and R7 and R8 are independently hydrogen, C1-5 alkyl, or C4-7 cycloalkylalkyl), among the above n number of R5 groups, two R5 groups bound to the same carbon atom become an oxygen atom to form oxo, or among the above m number of R4 groups and n number of R5 groups, two adjacent R4 groups, two adjacent R5 groups, or one R4 and one R5 groups may be bound to each other to form a benzene, pyridine, cyclopentane, cyclohexane, or cycloheptane fused ring (wherein at least one of m number of R4 groups and n number of R5 groups should be hydroxy, or two R5 groups bound to the same carbon atom should become an oxygen atom to form oxo);
R9 is hydrogen, C1-5 alkyl, C2-5 alkenyl, C7-13 aralkyl, C1-3 hydroxyalkyl, (CH2)pOR6, or (CH2)pCO2R6, wherein p and R6 are as defined above; and
R10 and R11 are bound to each other to form xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94CH2xe2x80x94, or R10 is hydrogen while R11 is independently hydrogen, hydroxy, C1-5 alkoxy, or C1-5 aliphatic acyloxy.
The present invention also provides a drug acting on xcex4 opioid receptor that comprises, as an active ingredient, an indole derivative represented by general formula (I) or a pharmaceutically acceptable salt thereof. The xe2x80x9cdrug acting on xcex4 opioid receptorxe2x80x9d used herein refers to a xcex4 opioid agonist or xcex4 opioid antagonist.
Examples of C1-5 alkyl used herein include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, and pentyl. Examples of C4-7 cycloalkylalkyl include cyclopropylmethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl, 4-cyclopropylbutyl, cyclobutylmethyl, and cyclohexylmethyl. Examples of C5-7 cycloalkenylalkyl include cyclobutenylmethyl, 2-cyclobutenylethyl, and 3-cyclobutenylpropyl. Examples of C6-12 aryl include phenyl, naphthyl, and tolyl. Examples of C7-13 aralkyl include benzyl, phenethyl, naphthylmethyl, and 3-phenylpropyl. Examples of C3-7 alkenyl include allyl, 3-butynyl, and phenyl. Examples of furan-2-yl-alkyl (wherein the alkyl moiety is C1-5) include 2-furylmethyl, 2-(2-furyl)ethyl, 1-(2-furyl)ethyl, and 3-(2-furyl)propyl. Examples of thiophen-2-yl-alkyl (wherein the alkyl moiety is C1-5) include 2-thienylmethyl, 2-(2-thienyl)ethyl, 1-(2-thienyl)ethyl, and 3-(2-thienyl)propyl. Examples of C1-5 alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, and pentyloxy. Examples of C2-5 alkoxy are the examples of C1-5 alkoxy except for methoxy. Examples of C1-5 aliphatic acyloxy include formyloxy, acetoxy, propionoxy, and pentanoyloxy. Examples of C7-13 aralkyloxy include benzyloxy, phenethyloxy, and naphthylmethoxy.
According to a preferred embodiment of the compound represented by general formula (I), R1 is C4-7 cycloalkylalkyl and C3-7 alkenyl, and C4-7 cycloalkylalkyl is more preferable. As another embodiment, R1 is hydrogen, C1-5 alkyl, C7-13 aralkyl, furan-2-yl-alkyl (wherein the alkyl moiety is C1-5), or thiophen-2-yl-alkyl (wherein the alkyl moiety is C1-5).
Among these preferred examples, hydrogen, C1-5 alkyl, C4-7 cycloalkylmethyl, C3-7 alkenyl, C7-13 aralkyl, furan-2-yl-alkyl (wherein the alkyl moiety is C1-5), or thiophen-2-yl-alkyl (wherein the alkyl moiety is C1-5) is more preferable. Hydrogen, methyl, phenethyl, 2-(2-furyl)ethyl (furan-2-yl-ethyl), or 2-(2-thienyl)ethyl (thiophen-2-yl-ethyl) is particularly preferred, and cyclopropylmethyl is also particularly preferable.
R2 is preferably hydrogen, hydroxy, acetoxy, propionoxy, methoxy, or ethoxy, and hydrogen, hydroxy, acetoxy, or methoxy is particularly preferred.
R3 is preferably hydrogen, hydroxy, or acetoxy, and hydroxy is particularly preferred.
xe2x80x94Zxe2x80x94 is preferably C2-5 alkylene.
R4 and R5 are preferably fluoro, chloro, bromo, iodo, nitro, C1-5 alkyl, hydroxy, C1-5 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, isothiocyanato, SR6, SOR6, SO2R6, (CH2)pOR6, (CH2)pCO2R6, SO2NR7R8, CONR7R8, (CH2)pNR7R8, or (CH2)pN(R7)COR8 (wherein p is an integer from 0 to 5; R6 is hydrogen or C1-5 alkyl; and R7 and R8 are independently hydrogen, C1-5 alkyl, or C4-7 cycloalkylalkyl). Particularly preferred is fluoro, chloro, bromo, iodo, nitro, methyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, hydroxymethyl, hydroxyethyl, isothiocyanato, mercapto, methylthio, methylsulfinyl, methylsulfonyl, methoxymethyl, ethoxymethyl, methoxyethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, sulfamoyl, dimethylsulfamoyl, dimethylcarbamoyl, dimethylamino, dimethylaminomethyl, dimethylaminoethyl, or amino. It is also preferable if two R5 groups bound to the same carbon atom become an oxygen atom to form oxo. Two adjacent R4 groups, two adjacent R5 groups, or one R4 and one R5 groups may be preferably bound to each other to form at least one benzene, pyridine, cyclopentane, cyclohexane, or cycloheptane fused ring. Particularly preferred groups form a benzene fused ring.
R9 is preferably hydrogen, C1-5 alkyl, allyl, or benzyl, and hydrogen or methyl is particularly preferred.
R10 and R11 are preferably bound to each other to form xe2x80x94Oxe2x80x94, or R10 is preferably hydrogen while R11 is hydrogen, hydroxy, or methoxy, and groups bound to each other to form xe2x80x94Oxe2x80x94 are particularly preferred.
The present invention, however, is not limited to these conditions.
The indole derivative represented by general formula (I) according to the present invention is a compound wherein at least one of m number of R4 groups and n number of R5 groups is hydroxy, or two R5 groups bound to the same carbon atom become one oxygen atom to form oxo. Specific examples of compounds are represented by {circle around (1)}, {circle around (2)}, and {circle around (3)} below.
{circle around (1)} A compound as exemplified in Compound 13 wherein R1, R2, R3, xe2x80x94Zxe2x80x94, R9, R10, and R11 are as defined in general formula (I); and one R4 group is hydroxy while the remaining 0 to 2 R4 groups and 0 to 10 R5 groups are independently fluoro, chloro, bromo, iodo, nitro, C1-5 alkyl, hydroxy, C1-5 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, isothiocyanato, SR6, SOR6, SO2R6, (CH2)pOR6, (CH2)pCO2R6, SO2NR7R8, CONR7R8, (CH2)pNR7R8, or (CH2)pN(R7)COR8 (wherein p is an integer from 0 to 5; R6 is hydrogen or C1-5 alkyl; and R7 and R8 are independently hydrogen, C1-5 alkyl, or C4-7 cycloalkylalkyl), two R5 groups bound to the same carbon atom become an oxygen atom to form oxo, or two adjacent R4 groups, two adjacent R5 groups, or R4 and R5 are bound to each other to form a benzene, pyridine, cyclopentane, cyclohexane, or cycloheptane fused ring.
{circle around (2)} A compound as exemplified in Compound 2 wherein R1, R2, R3, xe2x80x94Zxe2x80x94, R9, R10, and R11 are as defined in general formula (I); and one R5 group is hydroxy while the remaining 0 to 9 R5 groups and 0 to 3 R4 groups are independently fluoro, chloro, bromo, iodo, nitro, C1-5 alkyl, hydroxy, C1-5 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, isothiocyanato, SR6, SOR6, SO2R6, (CH2)pOR6, (CH2)pCO2R6, SO2NR7R8, CONR7R8, (CH2)pNR7R8, or (CH2)pN(R7)COR8 (wherein p is an integer from 0 to 5; R6 is hydrogen or C1-5 alkyl; and R7 and R8 are independently hydrogen, C1-5 alkyl, or C4-7 cycloalkylalkyl), two R5 groups bound to the same carbon atom become an oxygen atom to form oxo, or two adjacent R4 groups, two adjacent R5 groups, or R4 and R5 are bound to each other to form a benzene, pyridine, cyclopentane, cyclohexane, or cycloheptane fused ring.
{circle around (3)} A compound as exemplified in Compound 1 wherein R1, R2, R3, xe2x80x94Zxe2x80x94, R9, R10, and R11 are as defined in general formula (I); and two R5 groups bound to the same carbon atom become an oxygen atom to form oxo while the remaining 0 to 8 R5 groups and 0 to 3 R4 groups are independently fluoro, chloro, bromo, iodo, nitro, C1-5 alkyl, hydroxy, C1-5 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, isothiocyanato, SR6, SOR6, SO2R6, (CH2)pOR6, (CH2)pCO2R6, SO2NR7R8, CONR7R8, (CH2)pNR7R8, or (CH2)pN(R7)COR8 (wherein p is an integer from 0 to 5; R6 is hydrogen or C1-5 alkyl; and R7 and R8 are independently hydrogen, C1-5 alkyl, or C4-7 cycloalkylalkyl), two R5 groups bound to the same carbon atom become an oxygen atom to form oxo, or two adjacent R4 groups, two adjacent R5 groups, or R4 and R5 are bound to each other to form a benzene, pyridine, cyclopentane, cyclohexane, or cycloheptane fused ring.
A preferred example of {circle around (1)} above is a compound wherein R1 is hydrogen, C1-5 alkyl, C4-7 cycloalkylalkyl, C3-7 alkenyl, C7-13 aralkyl, furan-2-yl-alkyl (wherein the alkyl moiety is C1-5), or thiophen-2-yl-alkyl (wherein the alkyl moiety is C1-5); R2 is hydrogen, hydroxy, acetoxy, propionoxy, methoxy, or ethoxy; R3 is hydrogen, hydroxy, or acetoxy; xe2x80x94Zxe2x80x94 is C2-5 alkylene; one R4 group is hydroxy while the remaining 0 to 2 R4 groups and 0 to 10 R5 groups are independently fluoro, chloro, bromo, iodo, nitro, C1-5 alkyl, hydroxy, C1-5 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, isothiocyanato, SR6, SOR6, SO2R6, (CH2)pOR6, (CH2)pCO2R6, SO2NR7R8, CONR7R8, (CH2)pNR7R8, or (CH2)pN(R7)COR8 (wherein p is an integer from 0 to 5; R6 is hydrogen or C1-5 alkyl; and R7 and R8 are independently hydrogen, C1-5 alkyl, or C4-7 cycloalkylalkyl), two R5 groups bound to the same carbon atom become an oxygen atom to form oxo, or two adjacent R4 groups, two adjacent R5 groups, or R4 and R5 are bound to each other to form at least one benzene, pyridine, cyclopentane, cyclohexane, or cycloheptane fused ring; R9 is hydrogen, C1-5 alkyl, allyl, or benzyl; and R10 and R11 are bound to each other to form xe2x80x94Oxe2x80x94 or R10 is hydrogen while R11 is hydrogen, hydroxy, or methoxy. An example of a particularly preferable compound is one wherein R1 is hydrogen, methyl, cyclopropylmethyl, phenethyl, furan-2-yl-ethyl, or thiophen-2-yl-ethyl; R2 is hydrogen, hydroxy, acetoxy, or methoxy; R3 is hydroxy; xe2x80x94Zxe2x80x94 is C2-5 alkylene; one R4 is hydroxy while the remaining 0 to 2 R4 groups and 0 to 10 R5 groups are independently fluoro, chloro, bromo, iodo, nitro, methyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, hydroxymethyl, hydroxyethyl, isothiocyanato, mercapto, methylthio, methylsulfinyl, methylsulfonyl, methoxymethyl, ethoxymethyl, methoxyethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, sulfamoyl, dimethylsulfamoyl, dimethylcarbamoyl, dimethylamino, dimethylaminomethyl, dimethylaminoethyl, or amino, two R5 groups bound to the same carbon atom become an oxygen atom to form oxo, or two adjacent R4 groups, two adjacent R5 groups, or R4 and R5 are bound to each other to form a benzene fused ring; R9 is hydrogen or methyl; and R10 and R11 are bound to each other to form xe2x80x94Oxe2x80x94.
A preferred example of {circle around (2)} above is a compound wherein R1 is hydrogen, C1-5 alkyl, C4-7 cycloalkylalkyl, C3-7 alkenyl, C7-13 aralkyl, furan-2-yl-alkyl (wherein the alkyl moiety is C1-5), or thiophen-2-yl-alkyl (wherein the alkyl moiety is C1-5); R2 is hydrogen, hydroxy, acetoxy, propionoxy, methoxy, or ethoxy; R3 is hydrogen, hydroxy, or acetoxy; xe2x80x94Zxe2x80x94 is C2-5 alkylene; one R5 group is hydroxy while the remaining 0 to 9 R5 groups and 0 to 3 R4 groups are independently fluoro, chloro, bromo, iodo, nitro, C1-5 alkyl, hydroxy, C1-5 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, isothiocyanato, SR6, SOR6, SO2R6, (CH2)pOR6, (CH2)pCO2R6, SO2NR7R8, CONR7R8, (CH2)pNR7R8, or (CH2)pN(R7)COR8 (wherein p is an integer from 0 to 5; R6 is hydrogen or C1-5 alkyl; and R7 and R8 are independently hydrogen, C1-5 alkyl, or C4-7 cycloalkylalkyl), two R5 groups bound to the same carbon atom become an oxygen atom to form oxo, or two adjacent R4 groups, two adjacent R5 groups, or R4 and R5 are bound to each other to form at least one benzene, pyridine, cyclopentane, cyclohexane, or cycloheptane fused ring; R9 is hydrogen, C1-5 alkyl, allyl, or benzyl; and R10 and R11 are bound to each other to form xe2x80x94Oxe2x80x94 or R10 is hydrogen while R11 is hydrogen, hydroxy, or methoxy. An example of a particularly preferable compound is one wherein R1 is hydrogen, methyl, cyclopropylmethyl, phenethyl, furan-2-ylethyl, or thiophen-2-ylethyl; R2 is hydrogen, hydroxy, acetoxy, or methoxy; R3is hydroxy, xe2x80x94Zxe2x80x94 is C2-5 alkylene; one R5 is hydroxy while the remaining 0 to 9 R5 groups and 0 to 3 R4 groups are independently fluoro, chloro, bromo, iodo, nitro, methyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, hydroxymethyl, hydroxyethyl, isothiocyanato, mercapto, methylthio, methylsulfinyl, methylsulfonyl, methoxymethyl, ethoxymethyl, methoxyethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, sulfamoyl, dimethylsulfamoyl, dimethylcarbamoyl, dimethylamino, dimethylaminomethyl, dimethylaminoethyl, or amino, two R5 groups bound to the same carbon atom become an oxygen atom to form oxo, or two adjacent R4 groups, two adjacent R5 groups, or R4 and R5 are bound to each other to form a benzene fused ring; R9 is hydrogen or methyl; and R10 and R11 are bound to each other to form xe2x80x94Oxe2x80x94.
A preferred example of {circle around (3)} above is a compound wherein R1 is hydrogen, C1-5 alkyl, C4-7 cycloalkylalkyl, C3-7 alkenyl, C7-13 aralkyl, furan-2-yl-alkyl (wherein the alkyl moiety is C1-5), or thiophen-2-yl-alkyl (wherein the alkyl moiety is C1-5); R2 is hydrogen, hydroxy, acetoxy, propionoxy, methoxy, or ethoxy; R3 is hydrogen, hydroxy, or acetoxy; xe2x80x94Zxe2x80x94 is C2-5 alkylene; two R5 groups bound to the same carbon atom become an oxygen atom to form oxo while the remaining 0 to 8 R5 groups and 0 to 3 R4 groups are independently fluoro, chloro, bromo, iodo, nitro, C1-5 alkyl, hydroxy, C1-5 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, isothiocyanato, SR6, SOR6, SO2R6, (CH2)pOR6, (CH2)pCO2R6, SO2NR7R8, CONR7R8, (CH2)pNR7R8, or (CH2)pN(R7)COR8 (wherein p is an integer from 0 to 5; R6 is hydrogen or C1-5 alkyl; and R7 and R8 are independently hydrogen, C1-5 alkyl, or C4-7 cycloalkylalkyl), two R5 groups bound to the same carbon atom become an oxygen atom to form oxo, or two adjacent R4 groups, two adjacent R5 groups, or R4 and R5 are bound to each other to form at least one benzene, pyridine, cyclopentane, cyclohexane, or cycloheptane fused ring; R9 is hydrogen, C1-5 alkyl, allyl, or benzyl; and R10 and R11 are bound to each other to form xe2x80x94Oxe2x80x94 or R10 is hydrogen while R11 is hydrogen, hydroxy, or methoxy. An example of a particularly preferable compound is one wherein R1 is hydrogen, methyl, cyclopropylmethyl, phenethyl, furan-2-ylethyl, or thiophen-2-ylethyl; R2 is hydrogen, hydroxy, acetoxy, or methoxy; R3 is hydroxy; xe2x80x94Zxe2x80x94 is C2-5 alkylene; two R5 groups bound to the same carbon atom become an oxygen atom to form oxo while the remaining 0 to 8 R5 groups and 0 to 3 R4 groups are independently fluoro, chloro, bromo, iodo, nitro, methyl, hydroxy, methoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, hydroxymethyl, hydroxyethyl, isothiocyanato, mercapto, methylthio, methylsulfinyl, methylsulfonyl, methoxymethyl, ethoxymethyl, methoxyethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, sulfamoyl, dimethylsulfamoyl, dimethylcarbamoyl, dimethylamino, dimethylaminomethyl, dimethylaminoethyl, or amino, two R5 groups bound to the same carbon atom become an oxygen atom to form oxo, or two adjacent R4 groups, two adjacent R5 groups, or R4 and R5 are bound to each other to form a benzene fused ring, R9 is hydrogen or methyl; and R10 and R11 are bound to each other to form xe2x80x94Oxe2x80x94.
It should be noted that the present invention is not limited to the above conditions.
Examples of pharmaceutically preferable salts include such acid addition salts as: inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphate; organic carboxylic acid salts such as acetate, lactate, citrate, oxalate, glutarate, malate, tartarate, fumarate, mandelate, maleate, benzoate, and phthalate; and organic sulfonic acid salts such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and camphorsulfonate. Among them, hydrochloride, hydrobromide, phosphate, tartarate, methanesulfonate, or the like is preferably used, although salts are not limited to these examples. Further, the compound of the present invention can be used as alkali metal salt or organic ammonium salt when the compound has an acidic functional group such as carboxyl.
The metabolic rate of the compound according to the present invention is slow, and thus, excellent drug efficacy can be sustained for a long period of time.
Among compounds represented by general formula (I) according to the present invention, Compound (i) wherein R1 is cyclopropylmethyl, R2 is hydroxy, R3 is hydroxy, xe2x80x94Zxe2x80x94 is propano, m is 1, n is 0, R4 is 7xe2x80x2-hydroxy, R9 is hydrogen, and R10 and R11 are bound to each other to form xe2x80x94Oxe2x80x94
is designated as 17-cyclopropylmethyl-6,7-didehydro4,5xcex1-epoxy-5xe2x80x2,6xe2x80x2-dihydro-4xe2x80x2H-pyrrolo [3,2,1-ij]quinolino[2xe2x80x2,1xe2x80x2:6,7]morphinan-3,7xe2x80x2,14xcex2-triol.
Among compounds represented by general formula (I) according to the present invention, Compound (ii) wherein R1 is cyclopropylmethyl, R2 is hydroxy, R3 is hydroxy, xe2x80x94Zxe2x80x94 is propano, m is 0, n is 2, two R5 groups are 6xe2x80x2-oxo, R9 is hydrogen, and R10 and R11 are bound to each other to form xe2x80x94Oxe2x80x94
is designated as 17-cyclopropylmethyl-6,7-didehydro-4,5xcex1-epoxy-6xe2x80x2-oxo-5xe2x80x2,6xe2x80x2-dihydro-4xe2x80x2H-pyrrolo[3,2,1-ij]quinolino[2xe2x80x2,1xe2x80x2:6,7]morphinan-3,14xcex2-diol.
Among compounds represented by general formula (I) according to the present invention, Compound (iii) wherein R1 is cyclopropylmethyl, R2 is hydroxy, R3 is hydroxy, xe2x80x94Zxe2x80x94 is propano, m is 0, n is 1, R5 is 6xe2x80x2xcex1-hydroxy, R9 is hydrogen, and R10 and R11 are bound to each other to form xe2x80x94Oxe2x80x94
is designated as 17-cyclopropylmethyl-6,7-didehydro-4,5xcex1-epoxy-5xe2x80x2,6xe2x80x2-dihydro-4xe2x80x2H-pyrrolo[3,2,1-ij]quinolino[2,xe2x80x21xe2x80x2:6,7]morphinan-3,6xe2x80x2xcex1,14xcex2-triol.
The compound of the present invention also includes a compound represented by general formula (IA): 
wherein
R1, R2, and R3 are as defined in general formula (I); R4, R4xe2x80x2, R5, and R5xe2x80x2 are independently hydrogen, fluoro, chloro, bromo, iodo, nitro, C1-5 alkyl, hydroxy, C1-5 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, phenyl, isothiocyanato, SR6, SOR6, SO2 R6, (CH2)p OR6, (CH2)p CO2 R6, SO2NR7R8, CONR7R8, (CH2)pNR7R8, or (CH2)pN(R7)COR8 (wherein p is an integer from 0 to 5; R6 is hydrogen or C1-5 alkyl; and R7 and R8 are independently hydrogen, C1-5 alkyl, or C4-7 cycloalkylalkyl); and R5 and R5xe2x80x2 bound to the same carbon atom become an oxygen atom to form oxo or two of R4, R4xe2x80x2, R5, and R5xe2x80x2 are bound to each other to form a benzene, pyridine, cyclopentane, cyclohexane, or cycloheptane fused ring wherein at least one of R4, R4xe2x80x2, R5, and R5xe2x80x2 should be hydroxy, or R5 and R5xe2x80x2 bound to the same carbon atom should become an oxygen atom to form oxo.
According to the present invention, metabolic rate can be lowered by introducing hydroxy and/or oxo as R4 and/or R5. This enables excellent drug efficacy to be sustained for a long period of time, and thus, the frequency of administration can be lowered.
Specific examples of compounds represented by general formula (IA) are shown in Tables 1 to 17.
2-Thienylethyl as shown in Tables 8, 9, 16, and 17 indicates 2-(2-thienyl)ethyl.
The compound of the present invention also includes a compound represented by general formula (IB): 
wherein R1, R2, R3, R4, R4xe2x80x2, R5, and R5xe2x80x2 are as defined above.
Specific examples of compounds represented by general formula (IB) are shown in Tables 18 to 21.
The compound according to the present invention includes a compound represented by general formula (I) wherein R4 and R5 are bound to each other to form a fused ring and also includes a compound represented by general formula (IC): 
wherein R1, R2, R3, R4, R4xe2x80x2, R5, and R5xe2x80x2 are as defined above.
Specific examples of compounds represented by general formula (IC) are shown in Tables 22 to 25.
Specifically, the compound represented by general formula (I) according to the present invention can be produced by the method shown in Scheme 1. 
Specifically, the compound can be obtained by allowing a morphinan derivative represented by general formula (II) wherein R1, R2, R3, R9, R10, and R11 are as defined in general formula (I) to react with a hydrazine derivative represented by general formula (III) wherein xe2x80x94Zxe2x80x94, m, n, R4, and R5 are as defined in general formula (I) in a solvent in the presence of an acid catalyst.
Examples of solvents which can be used herein include: alcoholic solvents such as methanol, ethanol, 1-propanol, and 2-propanol; aprotic dipolar solvents such as DMF and DMSO; aromatic hydrocarbon solvents such as benzene, toluene, and xylene; ether solvents such as diethyl ether, THF, and DME; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; and organic acids that can be used as solvents such as acetic acid and propionic acid. Among these solvents, preferred are alcoholic solvents such as methanol, ethanol, 1-propanol, and 2-propanol; aprotic dipolar solvents such as DMF and DMSO; organic acids that can be used as solvents such as acetic acid and propionic acid. Methanol, ethanol, DMF, and acetic acid are particularly preferred.
Examples of acid catalysts which can be used include: inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, and hydroiodic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid; organic carboxylic acids such as acetic acid, lactic acid, citric acid, oxalic acid, glutaric acid, malic acid, tartaric acid, fumaric acid, mandelic acid, maleic acid, benzoic acid, and phthalic acid (incidentally, although the reaction may not smoothly progress with organic calboxylic acid alone, a strong acid may be optionally added as a cocatalyst in such a case); and acidic ion-exchange resin. Among these acid catalysts, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and acidic ion-exchange resin are preferably used. Furthermore, the equivalent ratio of the acid catalyst to be used relative to the total amount of base present in the reaction system is from 1 to 30, and preferably from 1 to 10. The acid catalyst may be added after converting the base component into salt, or may be added into the reaction mixture in a desired amount. The reaction temperature can be from 0xc2x0 C. to 300xc2x0 C., and preferably from 0xc2x0 C. to 170xc2x0 C. A range of 25xc2x0 C. to 120xc2x0 C. is particularly preferable.
Among the compounds represented by general formula (I) according to the present invention, a compound represented by general formula (Ia), wherein two R5 groups are bound to the same carbon atom to form oxo (wherein R1, R2, R3, R4, R9, R10, R11, and m are as defined in general formula (I); n is an integer from 0 to 8; xe2x80x94Z1xe2x80x94 and xe2x80x94Z2xe2x80x94 are independently a crosslinkage having 0 to 4 carbon atoms (wherein the total number of crosslinked carbons of xe2x80x94Z1xe2x80x94 and xe2x80x94Z2xe2x80x94 is 1 to 4)), and a compound represented by general formula (Ib) wherein one R5 group is hydroxy; (wherein R1, R2, R3, R4, R9, R10, R11, m, n, xe2x80x94Z1xe2x80x94, and xe2x80x94Z2xe2x80x94 are as defined above) can also be produced by the method shown in Scheme 2. 
Specifically, a morphinan derivative represented by general formula (II) wherein R1, R2, R3, R9, R10, and R11 are as defined above is reacted with a hydrazine derivative represented by general formula (IIIa) wherein xe2x80x94Z1xe2x80x94, xe2x80x94Z2xe2x80x94, m, n, R4, and R5 are as defined above; and R12 and R13 may be a carbonyl protecting group wherein both are methyl or acetyl, or R12 and R13 may be bound to each other to form a 1,3-dioxolan or 1,3-dioxane ring under the same reaction condition as in Scheme 1 to be converted into a compound represented by general formula (W) wherein R1, R2, R3, R4, R5, R9, R10, R11, R12, R13, m, n, xe2x80x94Z1xe2x80x94, and xe2x80x94Z2xe2x80x94 are as defined above, followed by deprotection of carbonyl that is commonly performed. Thus, Compound (Ia) can be obtained. When R12 and R13 are both methyl or a 1,3-dioxolan or 1,3-dioxane ring is formed through a R12xe2x80x94R13 bond, deprotection can be carried out by allowing a reaction to proceed in the presence of an acid catalyst in a solvent with, for example, water or acetone. When R12 and R13 are both acetyl, deprotection can be carried out by allowing a base to act in a solvent.
Compound (Ib) can be produced by causing a commonly used reducing agent in a solvent to act on Compound (Ia) obtained above, thereby converting carbonyl into hydroxy. Examples of a reducing agent include sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, and LS-selectride. Compound (Ib) can be obtained as a mixture of xcex1-hydroxy and xcex2-hydroxy, and they can be separated from each other by chromatography, recrystallization, or the like.
Among the compounds represented by general formula (I) according to the present invention, a compound represented by general formula (Ic), wherein two R5 groups are bound to a carbon atom adjacent to a benzene ring of indole to form oxo (wherein R1, R2, R3, R4, R5, R9, R10, R11, and m are as defined in general formula (I); n is an integer from 0 to 8; xe2x80x94Z3xe2x80x94 is a C1-4 crosslinkage), and a compound represented by general formula (Id), wherein one R5 group bound to a carbon atom adjacent to a benzene ring of indole is hydroxy, (wherein R1, R2, R3, R4, R5, R9, R10, R11, m, n, and xe2x80x94Z3xe2x80x94 is as defined above) can also be produced by the method shown in Scheme 3. 
Specifically, a morphinan derivative represented by general formula (II) wherein R1, R2, R3, R9, R10, and R11 are as defined above is reacted with a hydrazine derivative represented by general formula (V) wherein m and R4 are as defined above under the same reaction condition as in Scheme 1. Thus, a compound represented by general formula (VI) wherein R1, R2, R3, R4, R9, R10, R11, and m are as defined above can be produced.
A compound represented by general formula (VII) wherein R1, R2, R3, R4, R9, R10, R11, xe2x80x94Z3xe2x80x94, and m are as defined above, R14 is nitrile or CO2R15 wherein R15 is C1-5 alkyl can be synthesized by performing common alkylation of amino groups to Compound (VI). Examples of alkylation include a method wherein an alkylating agent represented by Xxe2x80x94Z3xe2x80x94R14 wherein R14 is as defined above; xe2x80x94Z3xe2x80x94 is a crosslinkage having 1 to 4 carbon atoms that may be optionally substituted with n number of R5 groups; and X is chloro, bromo, iodo, TsO, or MsO, or acrylic ester (CH2xe2x95x90CHxe2x80x94CO2R15 wherein R15 is as defined above) is reacted with a base in a solvent. In such a reaction, a reaction time can be shortened with the addition of phase-transfer catalysts such as tetrabutylammonium chloride or triethylbenzylammonium chloride.
R14 in a compound represented by general formula (VII) can be converted into carboxylic acid by hydrolyzing nitrile or ester, thereby obtaining a compound represented by general formula (VIII) wherein R1, R2, R3, R4, R9, R10, R11, xe2x80x94Z3xe2x80x94, and m are as defined above.
Compound (Ic) can be produced by cyclization of Compound (VIII). Cyclization can be carried out by common Friedel-Crafts acylation, and examples include the following two methods. Specific examples include (1) a method that is carried out by causing methanesulfonic acid and phosphorus pentoxide to act on Compound (VIII) and (2) a method that is carried out by converting the carboxylic compound (VIII) into an acid chloride using oxalyl chloride, thionyl chloride, or the like, and then causing acids such as aluminum chloride to act on the acid chloride.
Further, Compound (Id) can be produced by causing a common reducing agent in a solvent to act on Compound (Ic), and converting carbonyl into hydroxy. Examples of a reducing agent include sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, and LS-selectride. Compound (Id) can be obtained as a mixture of xcex1-hydroxy and xcex2-hydroxy, and they can be separated from each other by chromatography, recrystallization, or the like.
Among compounds represented by general formula (I) according to the present invention, a compound represented by general formula (If) wherein R1, R2, R3, R5, R9, R10, R11, and n are as defined in general formula (I); R4 is as defined in general formula (I) or hydrogen, and at least one of m number of R4 groups is hydroxy; xe2x80x94Zxe2x80x94 is a crosslinkage having 2 to 5 carbon atoms; and m is an integer from 1 to 3 can also be produced by the method shown in Scheme 4. 
Specifically, a morphinan derivative represented by general formula (II) wherein R1, R2, R3, R9, R10, and R11 are as defined above is reacted with a hydrazine derivative represented by general formula (IIIb) wherein xe2x80x94Zxe2x80x94, m, n, R4, and R5 are as defined above; and X1 is methoxy or bromo under the same reaction condition as in Scheme 1 to synthesize a compound represented by general formula (Ie) wherein R1, R2, R3, R4, R5, R9, R10, R11, m, n, xe2x80x94Zxe2x80x94, and X1 are as defined above. Subsequently, X1 in Compound (Ie) is converted into hydroxy, thereby producing Compound (If). Examples of methods for converting X1 into hydroxy include: when X1 is methoxy, a method that is carried out by causing a base such as CH3(CH2)2SK to act on Compound (Ie) in a solvent such as dimethylformamide, and a method that is carried out by causing acid such as BBr3 in a solvent such as dichloromethane. When X1 is bromo, an example of methods for converting X1 into hydroxy is a method that is carried out by causing an organic lithium compound such as n-butyl lithium to act on Compound (Ie) in a solvent such as THF to convert X1 into lithio, followed by oxidation thereof using nitrobenzene or the like, thereby converting X1 into hydroxy.
Among compounds represented by general formula (I) according to the present invention, a compound represented by general formula (Ig), wherein one R5 group bound to a carbon atom adjacent to a nitrogen atom is hydroxy (wherein R1, R2, R3, R4, R5, R9, R10, and R11 are as defined in general formula (I); xe2x80x94Z4xe2x80x94 is a crosslinkage having 1 to 4 carbon atoms; m is an integer from 0 to 3; and n is an integer from 0 to 8), can be also produced by the method shown in Scheme 5. 
Specifically, a morphinan derivative represented by general formula (II) wherein R1, R2, R3, R9, R10, and R11 are as defined above is reacted with a hydrazine derivative represented by general formula (IX) wherein m and R4 are as defined above, and xe2x80x94Z4xe2x80x94 is a crosslinkage having 1 to 4 carbon atoms that may be optionally substituted with n number of R5 groups under the same reaction condition as in Scheme 1. Thus, a compound represented by general formula (X) wherein R1, R2, R3, R4, R5, R9, R10, R11, xe2x80x94Zxe2x80x94, m, and n are as defined above can be synthesized. Subsequently, hydroxy in Compound (X) is oxidized to convert into aldehyde. This allows the cyclization to proceed, and thus, Compound (Ig) can be obtained. An example of oxidation that can be preferably used is Swem oxidation. Compound (Ig) can be obtained as a mixture of xcex1-hydroxy and xcex2-hydroxy, and they can be separated from each other by chromatography, recrystallization, or the like.
The indole derivative represented by general formula (I) according to the present invention is useful as a pharmaceutical. Specifically, it can be used as a drug acting on xcex4 opioid receptor, i.e., as a xcex4 opioid receptor agonist or xcex4 opioid receptor antagonist. Since the compound according to the present invention selectively acts on the xcex4 opioid receptor, it can be used as an agent such as an analgesic, antitussive, immunosuppressive agent, or brain-cell-protecting agent that does not exhibit side effect resulting from a xcexc or xcexa opioid receptor such as drug dependence, suppression of the CNS, constipation, respiratory depression, drug aversion, or psychotomimetic effects.
When the compound of the present invention is used as an agent such as an analgesic, antitussive, immunosuppressive agent, or brain-cell-protecting agent in clinical practice, the agent may be a free base or its salt per se. Alternatively, an additive such as an excipient, stabilizer, preservative, buffer, solubilizing agent, emulcifier, diluent, or isotonizing agent may be suitably mixed. Examples of dosage forms include: oral preparations such as tablets, capsules, granules, powders, or syrups; parenteral preparations such as injections, suppositories, or liquid drugs; and local administration by ointments, cream pharmaceuticals, patches, or the like. The agents relating to xcex4 opioid receptors such as analgesics, antitussives, immunosuppressive agents, or brain-cell-protecting agents according to the present invention comprise the aforementioned active ingredient in amounts of preferably 0.00001 to 90% by weight, and more preferably 0.0001 to 70% by weight. Amounts used may be suitably selected depending on symptom, age, body weight, medication method, etc. In the case of injections, the amount of active ingredients is 0.1 xcexcg to 1 g and 1 xcexcg to 10 g in the case of oral preparations per day per adult. These preparations can be administered in one dose or several separate doses.
This description includes part or all of the contents as disclosed in the description of Japanese Patent Application No. 2000-356382, which is a priority document of the present application.
The present invention is hereafter described in more detail with reference to examples. These examples, however, are not intended to limit the technical scope of the present invention.